Multimodal profiling of lung granulomas in macaques reveals cellular correlates of tuberculosis control

Mycobacterium tuberculosis lung infection results in a complex multicellular structure: the granuloma. In some granulomas, immune activity promotes bacterial clearance, but in others, bacteria persist and grow. We identified correlates of bacterial control in cynomolgus macaque lung granulomas by co-registering longitudinal positron emission tomography and computed tomography imaging, single-cell RNA sequencing, and measures of bacterial clearance. Bacterial persistence occurred in granulomas enriched for mast, endothelial, fibroblast, and plasma cells, signaling amongst themselves via type 2 immunity and wound-healing pathways. Granulomas that drove bacterial control were characterized by cellular ecosystems enriched for type 1-type 17, stem-like, and cytotoxic T cells engaged in pro-inflammatory signaling networks involving diverse cell populations. Granulomas that arose later in infection displayed functional characteristics of restrictive granulomas and were more capable of killing Mtb. Our results define the complex multicellular ecosystems underlying (lack of) granuloma resolution and highlight host immune targets that can be leveraged to develop new vaccine and therapeutic strategies for TB.

Automated summary

This study focuses on tuberculosis lung infection and its complex multicellular structure, the granuloma. Through various techniques, the study identifies factors that influence bacterial control in granulomas. It shows that granulomas with bacterial persistence are enriched with different cell types that communicate through immune and wound-healing pathways. On the other hand, granulomas that drive bacterial control are characterized by diverse cell populations engaged in pro-inflammatory signaling networks. The study also finds that granulomas that arise later in infection display characteristics of restrictive granulomas and are more effective at killing Mycobacterium tuberculosis.